A directed TM->JM coupling in receptor tyrosine kinase dimers, set by activating mutations and the membrane environment
- 1Kyoto Pharmaceutical University
Abstract
The direction of conformational coupling in a membrane protein, that is, which domain drives which, has been inaccessible to experiment. We recover this directivity from molecular dynamics (MD) of transmembrane-juxtamembrane (TM-JM) dimers of receptor tyrosine kinases EGFR and FGFR3. Coupling is detected with a Bayesian-network framework (CASCADE); its direction is measured with PERI (Phase-plane Estimation of Rotational Irreversibility), the net phase-plane circulation, validated on synthetic data and resolved at 0.1 ns. Direction is summarized as the TM[->]JM directed-mass fraction f+ (0.5 = balanced) via a hierarchical Bayesian model. The activating TM mutants EGFR L658Q and FGFR3 A391E are TM-JM (posterior probability 0.95 and 0.99); fluid wild-type EGFR leans the same way (0.93), in agreement with its experimentally reported constitutive activity in fluid but not ordered bilayers; the ligand-dependent ordered wild type is balanced (0.45); and an activating mutation raises the TM-JM bias above the ordered wild type with probability 0.94. The directivity thus tracks the measured activity state of the receptor, distinguishing signaling-competent from ligand-dependent RTK dimers by a property not apparent from structure alone.
Versions
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BibTeX
@misc{sato2026directed,
title = {{A directed TM->JM coupling in receptor tyrosine kinase dimers, set by activating mutations and the membrane environment}},
author = {T. Sato and H. Tamagaki-Asahina},
howpublished = {bioRxiv},
year = {2026},
month = may,
doi = {10.64898/2026.05.22.727318},
url = {https://www.biorxiv.org/content/10.64898/2026.05.22.727318v2},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - A directed TM->JM coupling in receptor tyrosine kinase dimers, set by activating mutations and the membrane environment
AU - T. Sato
AU - H. Tamagaki-Asahina
PY - 2026
DA - 2026/05/22
PB - bioRxiv
DO - 10.64898/2026.05.22.727318
UR - https://www.biorxiv.org/content/10.64898/2026.05.22.727318v2
AB - The direction of conformational coupling in a membrane protein, that is, which domain drives which, has been inaccessible to experiment. We recover this directivity from molecular dynamics (MD) of transmembrane-juxtamembrane (TM-JM) dimers of receptor tyrosine kinases EGFR and FGFR3. Coupling is detected with a Bayesian-network framework (CASCADE); its direction is measured with PERI (Phase-plane Estimation of Rotational Irreversibility), the net phase-plane circulation, validated on synthetic data and resolved at 0.1 ns. Direction is summarized as the TM[->]JM directed-mass fraction f+ (0.5 = balanced) via a hierarchical Bayesian model. The activating TM mutants EGFR L658Q and FGFR3 A391E are TM-JM (posterior probability 0.95 and 0.99); fluid wild-type EGFR leans the same way (0.93), in agreement with its experimentally reported constitutive activity in fluid but not ordered bilayers; the ligand-dependent ordered wild type is balanced (0.45); and an activating mutation raises the TM-JM bias above the ordered wild type with probability 0.94. The directivity thus tracks the measured activity state of the receptor, distinguishing signaling-competent from ligand-dependent RTK dimers by a property not apparent from structure alone.
ER -